INTRODUCTION
CASE IN DETAIL
RW’s problems started 11 years ago when he was incidentally diagnosed with Hodgkin’s disease when admitted to hospital with a traumatic injury related to a motor vehicle accident. His Hodgkin’s disease was treated with mantle radiotherapy alone on subsequent biopsy and staging. He denies any side effects associated with this treatment.
He was well until 7 months ago, when he presented to his general practitioner with retrosternal discomfort. He could recall experiencing drenching night sweats over the days preceding his presentation, but denied fevers or known weight loss. Chest X-ray performed subsequently showed mediastinal widening suggestive of mediastinal lymphadenopathy and he was referred to a haematologist, who diagnosed recurrent Hodgkin’s disease. He has had multiple investigations, including lymph node biopsy, CT of thorax and abdomen, a gallium scan and bone marrow biopsy. He was immediately commenced on the ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) combination chemotherapeutic regimen. He showed good disease response, with disappearance of symptoms as well as lymphadenopathy on follow-up imaging. His treatment was prematurely terminated after three cycles (5 months ago) due to his developing bleomycin-associated pneumonitis. At this stage he denied any respiratory symptoms. The lung toxicity was discovered on routine screening with the carbon monoxide diffusion capacity test.
Four and a half months ago he was commenced on the MOPP (mechlorethamine, vincristine, procarbazine, prednisone) combination chemotherapy regimen. He suffered side effects of nausea, vomiting and alopecia associated with this treatment. He also experienced easy bruising and oral candidiasis associated with the steroid use, but denied any mood swings or insomnia. He has not been investigated for diabetes or osteoporosis. After three cycles of therapy, 2 months ago he was admitted to hospital with high fevers and was diagnosed with febrile neutropenia. During this admission he was also treated in the intensive care unit for 5 days. He could not recollect in detail the events surrounding this episode and the treatment he received. After 2 weeks in hospital he was discharged on prophylactic trimethoprim and sulfamethoxazole one tablet daily. He has been compliant with this treatment and denies any associated side effects.
He had his fourth cycle of chemotherapy without any complications. He is currently waiting for his fifth and final cycle of MOPP, the administration of which has not been planned as yet. He has had a PET scan 1 week ago and has been told by the haematologist that he still has some residual disease activity. He currently suffers from extreme lethargy, weakness and exertional dyspnoea on walking 100 metres on flat ground. He has lost a total of 10 kg over the past 7 months.
His medication summary includes trimethoprim/sulfamethoxazole and occasional paracetamol. He denies any known allergy to medications.
His father is alive at the age of 71 and suffers from ischaemic heart disease. His mother is 69 and suffers from severe rheumatoid arthritis. He has only one sister, who is well at the age of 36. He has no family history of malignancy.
He worked as a private security guard until 6 months ago. He is currently unemployed and survives on a single-parent benefit from the government. He finds it difficult to meet his and his family’s needs with this income.
He has never smoked. He previously consumed 100 g of alcohol per day in the form of beer and did so for approximately 10 years. He has not consumed any alcohol during the past 7 months. Prior to his current diagnosis he denies experiencing any lymph node pain associated with alcohol consumption.
He separated from his wife 2 years ago. Before that he was married for 3 years. He has two children, a boy aged 5 and a girl aged 4, both of whom live with him. His mother looks after his children when he is in hospital. She finds it difficult to continue supporting him due to her debilitating arthritis.
He is independent with daily activities and drives too. He lives in a house for which he is paying off a mortgage.
He has never been depressed, even with the current diagnosis and the stormy course he has had. He is very positive about the future. His main problem, as he identifies it, is finding enough finances to support his family and to pay off the mortgage. His only social support is his ailing mother.
The dietary history suggests satisfactory nutrition. He has good insight into his disease and the chances of survival and cure as well as the toxicities associated with his treatment.
ON EXAMINATION
RW was alert and cooperative. He was alopecic and cushingoid. He had a portacath in the inner aspect of his left forearm and the site was not inflamed.
His pulse rate was 50 beats per minute and was regular in rhythm and normal in character. His blood pressure was 125/80 mmHg and there was no postural drop. His respiratory rate was 12 per minute at rest. He was afebrile. His estimated body mass index was 28 and his cognition was intact, with a Mini-Mental State score of 30/30.
He did not have any palpable lymphadenopathy. There was no mucositis or mucosal pallor. He had multiple ecchymoses, particularly in the dorsal aspects of his forearms and the thighs. He had a buffalo hump, but there was no bony tenderness or kyphoscoliosis.
His respiratory system examination showed reduced but symmetrical expansion of the upper and lower thorax. His lung fields were resonant throughout and the breath sounds were vesicular. There was fine early inspiratory crepitation in the lower zones bilaterally that did not clear with coughing.
In his cardiovascular system examination, the jugular venous pressure was not elevated. He had two heart sounds of normal intensity and no third heart sound or pericardial rub. There was no peripheral oedema.
His gastroenterological system examination was remarkable for oral thrush but his abdomen was soft, not distended and non-tender. There was no organomegaly or palpable mass.
Neurological examination showed normal visual acuity and normal fundoscopy bilaterally. The rest of the cranial nerve examination was unremarkable. His upper limb motor examination showed normal tone, power (surprisingly, even in the proximal musculature) and coordination. His reflexes were depressed at all levels symmetrically. Sensory function was intact.
Lower limb examination showed proximal weakness of 4/5 bilaterally with depressed reflexes at all levels. His coordination and sensation to all modalities were preserved. His plantar reflexes were flexor bilaterally and his gait was normal. However, he was unable to stand up from the squatting position without assistance.
His musculoskeletal examination was unremarkable.
He belongs to stage 1 of the ECOG (Eastern Cooperative Oncology Group) performance scale.
In summary, this is a 40-year-old man with recurrent Ann Arbor stage 4 Hodgkin’s disease, with poor tolerance to first-line chemotherapy and inadequate response to second-line therapy, of which the course was complicated by a serious episode of febrile neutropenia. He also has significant social problems, including financial difficulties. Although his prognosis appears to be guarded, he is optimistic.
The main issue with this man is achieving disease remission and addressing the complications of chemotherapy.
To approach the management of this man I have identified three acute medical problems and one social problem. I have also identified two long-term medical problems and a social problem:
To decide on the best treatment protocol to achieve disease remission, I would like to look at the histology report of the lymph node biopsy he had during the initial work-up, and also the results of the staging investigations, including the bone marrow biopsy and the most recent gallium scan, to see where the residual disease activity is localised.
According to the history, I believe that this man has presented with Ann Arbor stage 4 disease. He has not tolerated first-line chemotherapy with the ABVD combination. He has incomplete response to the conventional MOPP combination.
The mainstay of his management now is to restage the disease and decide on salvage therapy. Salvage therapeutic options to be considered include alternative chemotherapy regimens such as the BEAM (carmustine, etoposide, cytarabine and melphalan) or BEACOP (bleomycin, etoposide, adriamycin, cyclophophamide, vincristine, prednisolone) combinations or autologous or allogenic bone marrow transplantation. The main concern here is whether this man would be able to tolerate such aggressive therapy given his compromised organ function and physical status.
To restage his disease I would do the following investigations:
I would also like to see the results of his recent PET scan.
To address the issue of organ damage, I would like to assess his current functional status by looking at the results of the following:
If the degree of organ damage is significant, further therapy with agents having similar toxicity is absolutely contraindicated. This poses the challenge of looking for suitable chemotherapeutic agents for ongoing therapy. This is especially important if the option of myeloablative therapy with stem cell infusion is to be considered.
To prevent further cardiac damage it is important to identify and strictly control RW’s coronary risk factor profile, given his previous mantle radiotherapy and the family history of coronary disease.
Focusing on the bleomycin lung, if the CT shows evidence of pneumonitis with a ground glass appearance of the lung parenchyma, high-dose corticosteroid therapy could be considered, to prevent further damage. But if it shows established fibrosis with the appearance of honeycombing, that will mean that irreversible damage has been done. He should be given pulmonary rehabilitation to optimise the function of the residual lung tissue.
It is important to assess the side effects he has suffered from corticosteroid therapy. I am interested in his fasting blood sugar levels and the bone densitometry results.
On achieving disease remission, long-term issues of management will become important. Regular clinical review with history and physical examination would suffice for the surveillance of recurrence. Due to his exposure to cytotoxic therapy, particularly with alkylating agents, he needs to be watched for the occurrence of acute myeloid leukaemia during the first 4 years. Non-Hodgkin’s lymphoma becomes an issue after about 10 years and solid cancers after about 15 years.
The mantle radiation therapy he received more than 10 years ago has the potential to cause hypothyroidism, and this should be checked for.
To address the social problems I want to consult the hospital social worker first, to assess the degree of financial difficulty this man is currently facing. It is necessary to explore other possible sources of income, including income protection schemes and government welfare schemes.
Given his adverse prognostic outlook, the issue of possible death and dying as well as the care of his children in such an eventuality should be discussed with the patient, with the support of the social worker and a counsellor. Advance directives regarding his finances and assets, a living will and power of attorney, as well as a legal guardian for decisions regarding medical treatment in case of incapacity, should also be discussed.
Questions and answers
Q: How would you have managed this man when he presented with high fevers and a neutrophil count of 2 × 109/L one month ago?
A: This is a case of febrile neutropenia, and my management approach would be first to perform a comprehensive septic work-up. This would include a detailed history, a thorough physical examination aimed at finding a septic focus, and investigations in the form of three sets of both aerobic and anaerobic blood cultures taken from separate sites at different times (one set taken from the portacath), urine analysis followed by microscopy and culture, and a chest X-ray. I would commence this man on empirical antibiotic therapy pending the investigation results. The agents that I would use include two broad-spectrum agents that would cover Gram-positive organisms (most common causative organisms in the setting of neutropenia are Gram-positive) as well as Gram-negative organisms, including Pseudomonas aeruginosa (Pseudomonas causes most mortality). My choice would be ticarcillin with clavulanic acid or imipenem with cilastin together with an aminoglycoside (gentamicin 5 mg per kg daily with daily serum levels) given intravenously. If the patient does not defervesce within 24 hours of commencement of the above antibiotic regimen I would add vancomycin 1 g intravenously to cover for possible methicillin-resistant Staphylococcus aureus.
Q: What concerns would you have if he were to need intubation and ventilation?
A: Bleomycin lung is susceptible to oxygen toxicity, so I would be inclined to use the minimum amount of oxygen that would maintain arterial oxygen saturation above 95% for the minimum period necessary. In addition, it is important to guard against barotrauma to his diseased lungs from high inspiratory pressures.
Q: What other treatment options do you have for this man’s malignancy?
A: Given the aggressive and resistant nature of his disease, he needs aggressive therapy to achieve complete remission. I would prefer autologous bone marrow transplantation following myeloablative chemotherapy.
Q: What does he think about the possibility of dying and what plans does he have for the care of his children?
A: This patient strongly believes that he will survive this illness. However, it is necessary to discuss this topic with the patient and cooperate with the social worker to formulate an action plan. This plan should initially include a conference with the participation of the patient, the social worker, his mother, who happens to be his main social support, and if possible his former wife.
Q: Can you please describe this chest X-ray?
A: The frontal view chest X-ray of RW taken on (insert date) shows diffuse non-confluent opacification of the lower zones of the pulmonary parenchyma bilaterally. This appearance is consistent with consolidation, acute pneumonitis, fibrosis or atelectasis. I would like to see the high-resolution CT of the chest for further clarification.
Q: What do you think about this CT scan?
A: There are changes seen in the lower zones, particularly in the lower lobes bilaterally extending from the peripheries. These are areas of honeycombing surrounding scattered islands of ground glass appearance. This picture is consistent with fibrosis of the lower lobes with areas of active pneumonitis scattered in between.
Q: You said that he has lost weight. Do you think he is malnourished?
A: Despite significant weight loss, this man still weighs 90 kg. He did not have clinical findings consistent with malnourishment and nutrient deficiency in the form of angular stomatitis, cheilosis, and atrophic glossitis or diffuse dermatitis. Although I did not measure his mid-arm circumference, I judged him to have satisfactory muscle bulk and power in that region. So this man is not malnourished currently.
Q: Did he have any B symptoms when he initially presented 11 years ago?
A: No, the diagnosis of Hodgkin’s disease was incidental on that occasion.
Q: What issues would you discuss with a young patient who was offered cytotoxic chemotherapy?
A: Cytotoxic chemotherapy can lead to gonadal damage and infertility, particularly in the male patient. Therefore I would counsel the patient regarding this and offer sperm banking or ova banking if future reproduction was anticipated. I would also seek professional psychological counselling, if needed, for the patient and their partner.
